Rapamycin and the gut microbiome

A very important study out of Columbia University shows that sugar , at least in part, leads to metabolic diseases by reducing TH 17 immune cells in the gut.

It seems that segmented filamentous gut bacteria leads to an increase in these TH17 cells which are responsible for reducing gut inflammation and maintaining metabolic health.

It’s been known for some time that rapamycin increases segmented filamentous gut bacteria, and now we know the significance of that change.

Among the most notable changes in fecal bacterial DNA content seen in the global microbiome analysis was a significant increase in prevalence of segmented filamentous bacteria (SFB, Candidatus Arthromitus sp.) in the rapamycin treated animals (Figure 6A, Figure 6—figure supplement 2A). SFB are intestinal Gram-positive bacteria with a segmented and filamentous morphology, and are not normally present at high levels in aged mice (Ericsson et al., 2014). The SFB genome lacks a majority of virulence factors and SFB are not invasive (Prakash et al., 2011); however, their tight adhesion to the intestinal epithelial cell induces differentiation of host immune cells (Atarashi et al., 2015). The increase in SFB following rapamycin treatment was confirmed by real-time PCR of DNA from fecal samples obtained from both mice receiving injections or encapsulated rapamycin (Figure 6B, Figure 6—figure supplement 2B), as well as by semi-quantitative histological scoring of the small intestine in an independent cohort of mice obtained from the Harrison Lab at the Jackson Laboratory and injected with 8 mg/kg/day of for 3 months at the University of Washington (Figure 6C,D,

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This is interesting and helpful to me, but does not explain why people have more trouble with T2D while on Rapa. Why does blood glucose go up? Maybe it’s transient and you just have to wait for it to settle down.

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With rapamycin the body is compensating, like in a prolonged fast or starvation state , by elevating glucose since the brain can’t function without it. That’s different from an actual disease like DM resulting in hyperglycemia.

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Luckily I didn’t develop T2D being on Rapa for 12 years. Most who I know did. Could be diet. Would be helpful to know the reasons.

I agree, but here you’re talking about daily doses of Rapa for organ transplant patients, right? That’s a different thing and dosing once a week is supposed to fix that.

On this forum it seems that people have more trouble with blood sugar after Rapa, even with weekly or biweekly dosing.

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@Bicep @rivasp12 Could it be possible that by inhibiting mTOR, it decreased mTOR stimulators like insulin thus increasing glucose periodically? I have not seen anything about Rapamycins effect on insulin, just glucose.

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Yes and no. Transplant patients usually take it daily for life without any breaks. It’s not how I take it. I have a 7 day break after each 4 days of taking 1mg/day. It could be a reason why I don’t have glucose problems or any side effects and, at the same time, it’s very beneficial for my transplanted kidney. Or it could be diet or combination of the two.

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Mtor inhibitors are well documented to cause diabetes, hyperglycemia, and increased blood sugar–basically the whole spectrum of elevated blood sugar effects. This is due to at least two mechanisms. First, it acts on beta cells in the pancreas to suppress insulin release. Second, it causes insulin resistance in other cells by suppressing the insulin signaling pathway.

There’s a myth I see floating around longevity circles a lot that this is a pseudo diabetes without harmful effects, but I see no reason to believe that is the case, except a wish for it to be so! In models organisms and human patients, as far as I have investigated, we see the expected deleterious effects of elevated sugars. Those effects can be mitigated in part or full by metformin, which also has longevity benefits. Of course, then people are less excited about the effects of metformin on muscle building and GI side effects.

In short, we don’t have perfect drugs. Expect anything you try to have serious downsides, and blood sugar monitoring is a must for rapa treatment, IMO.

Longevity research is in its infancy, and proceeding very slowly (even by science standards) for a variety reasons. On the other hand, the recent movement at NIH towards focusing on “senescence” holistically, instead of just individual diseases, seems like a strong signal to me that at the very least the field is starting to shed its fringe-y stigma.

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The effects of rapamycin on pancreas physiology, insulin, and glucose are complex and show individual variation.

It has also been demonstrated that rapamycin protects against end organ damage of diabetes such as nephropathy and retinopathy.

https://www.tandfonline.com/doi/pdf/10.4161/cc.10.24.18595

Certainly no evidence that weekly dosing gives DM in healthy adults.

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Folks asked what the mechanism was, and I knew it from the literature, so supplied a brief answer. You can certainly delve much deeper into those pathways than the two sentences I provided.

And of course it’s individual–all pharmacology is. That doesn’t mean the mechanism is unknown, it means it has a variable amount of impact on individuals. Even in cancer patients it only causes outright diabetes about 10-15% of the time. That said, there is a ton of evidence that it affects blood sugar negatively across many species and at many doses.

Does that include healthy humans taking low weekly doses? No, because we have essentially no evidence of that kind at all. If you are willing to extrapolate from what is experimentally known to say that rapa taken this way is likely to prolong life, I would suggest that the evidence that it can raise blood sugar in a detrimental way is at least as good and potentially better, given that it is an effect that has at least been studied in humans in vivo. Based on the lack of any evidence to the contrary, feel 100% comfortable recommending that you monitor your blood sugar if you are taking rapa experimentally, and take elevation seriously.

I’ve observed that the rapa community has an unhealthy true-believer tendency to automatically reject experiments with bad news or deleterious effects, and accept unconditionally those that show benefits. I’ve seen elsewhere this kind of defensive reaction when I’ve posted a study showing negative side effects or lack of efficacy. I think people are so invested in making a choice counter to mainstream medical recommendations that they feel it is almost a personal attack, like I’m questioning their personal judgment. I’m not. I’m here to explore, but that means the WHOLE body of literature and evidence to me. Confirmation bias and motivated thinking are natural and universal cognitive biases, but if we don’t actively fight them to remain as objective as possible, then we leave the realm of science and become a cult.

I think overall the research looks really good–good enough for me to plan to experiment personally. It’s not like we’ve got unlimited time to wait for science to deliver the gold standard of evidence here! But I always keep in mind the fact that I’m making a guess, based on science that is far from mature, and that guess could very well be wrong. I think it’s very tempting to reduce the discomfort of living with that uncertainty by narrowing focus to just the good news–to make your decision and then just keep reconfirming it. But I think we have to resist that tendency. It doesn’t helps us make better guesses or live longer lives when we cherrypick only the positive data to add to our understanding or predictions, and try to wave away the risks.

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In one of the recent videos with Dr. Green, he was asked whether rapamycin decreased the insulin production in his patients. I believe his answer was, yes in all of them. He requires a fasting insulin test for all of his patients.

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You make some valid and very important points - also concerning confirmation bias and motivated thinking.
Your post does make me wonder how, with such apparent effects on blood sugar levels, Rapa still results in an increase in lifespan in so many species, in so many studies?

I will definitely start measuring my BG-levels again (instead of just relying on Hba1c once per 4 months). And personally I will stick with an anti-diabetic drug while I’m taking Rapamyin, just in case.

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I’d say that diabetes as a disease entity is more than just hyperglycemia. In those with diabetes for over 50 years, the vast majority don’t get kidney disease, majority don’t get heart disease, and a sizable minority don’t get retinopathy or neuropathy. None of the complications correlate very well with glucose levels gone awry. It’s a complicated disease entity.

https://www.diabetesincontrol.com/why-some-diabetes-patients-have-no-complications-even-after-50-years/

Furthermore, it’s almost always associated with obesity, causing us to classify type 2’s as diabesity. Obesity further complicates the picture.

I think we’re starting to gather some good information on this site about the percentage of rapamycin intermittent users that have any degree of glucose dysfunction. Matt K. will also have some data on this.

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This is a Gary Taubes article:

https://sci-hub.se/https://doi.org/10.1126/science.322.5900.365

Basically 3 huge trials of controlling blood sugar and there was such a bad response some of them were stopped. They didn’t control the insulin though, which is probably the bad guy.

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From MB:

mTOR is a part of a nutrient-sensing pathway [23-27]. Nutrients and insulin activate mTOR. Rapamycin, which inhibits mTOR, is a “starvation-mimetic”, making the organism “think” that food is in a short supply. The most starvation-sensitive organ is the brain. The brain consumes only glucose and ketones. Therefore, to feed the brain during starvation, the liver produces glucose from amino acids (gluconeogenesis) and ketones from fatty acids (ketogenesis). Since insulin blocks both processes, the liver needs to become resistant to insulin. Also secretion of insulin by beta-cells is decreased. And adipocytes release fatty acids (lipolysis) to fuel ketogenesis by the liver. Thus, there are five noticeable metabolic alterations of starvation: gluconeogenesis, ketogenesis, insulin resistance, low insulin levels and increased lipolysis. This metabolic switch is known as starvation diabetes, a reversible condition, described 160 years ago (see for references [28]). Starvation diabetes could be explained by deactivation of mTOR, which otherwise is activated by nutrients. In theory, rapamycin can cause similar symptoms in the presence of nutrients.

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Excellent article Bicep and my point exactly. There’s clearly more to diabetes than elevated glucose and this is certainly supported by studies showing Increased mortality with strict glucose control. Also, if glucose were the whole story then the vast majority, if not all, of diabetics would get end organ damage, but they don’t. Prediabetics almost never get microvascular complications.

Elevation of glucose is an unusual event in intermittent rapamycin users and seems modest in most cases. This isn’t the disease entity of diabetes. In animal studies where elevations of glucose are observed, they still live longer and healthier., not so with diabetics.

The highest FGL I have had after taking rapamycin at relatively high levels of rapamycin, at various dosages of >5mg/wk. The highest FGL I have experienced was 112 mg/dL and that was a one-time reading. My normal fasting glucose is 97 mg/dL and that is on a time-restricted diet which tends to give higher morning FGL levels.

Given the fact that I am in an age group more prone to developing type II DM, I am not worried about rapamycin’s relatively benign increase in my fasting blood glucose levels as it has also increased my HDL readings. What is much more disturbing to me is how much rapamycin has increased my LDL, still in the high normal, and the big increase in triglycerides which are now outside of the high normal range.

My A1c levels have never exceeded the normal range. Oddly, my lowest A1c level was 5.2% after taking 20 mg of rapamycin with GFJ bi-weekly.

Interestingly this study says that higher HDL levels are associated with a lower risk of diabetes.

“► Contrastingly, high level of high-density lipoprotein cholesterol significantly decreased risk of DM in patients with impaired fasting glucose.”

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I could cite to numerous discussions by respected doctors for the proposition that insulin resistance manifested by pre-diabetes and type two diabetes is one of the primary causes of all of the so-called age related diseases. It’s not something to be cast off casually. That is not to say that decreased insulin levels and increased glucose as a result of rapamycin is the same thing. But it does mean that insulin sensitivity is even more important.

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I’d certainly be the last person to argue with respected doctors, but my point still remains that there’s more to the disease entity of diabetes than just hyperglycemia. We still don’t really know why some go on to develop end organ damage while others don’t. Nor do we understand why strict glycemic controlled in the Accord study increased mortality rates.
It’s not a simple thing, but regardless , it’s certainly not evident that the increase in glucose, which is usually fairly modest and uncommon in rapamycin intermittent users, presents even a fraction of the risk of actual diabetes.

I don’t disagree with anything you said in your post. You were talking about type 1 diabetes. The study you linked was talking about type one diabetes. That is a completely different animal. Those people do not produce insulin. I was referencing type two diabetes. And that is tremendously damaging. Metabolic syndrome is upstream of that disease. It is a shame they share the same name.